Process for the preparation of diphenyl ether compounds

ABSTRACT

A process for producing fomesafen from acifluorfen comprises the steps of (a) converting acifluorfen to its acid chloride, (b) coupling the acid chloride so formed with methanesulphonamide to form crude fomesafen and (c) purifying the crude fomesafen, characterized in that each of the steps is carried out in a single common solvent, which is preferably a chloroalkane. Preferably the steps are telescoped together so that there is no isolation of the product for any step until fomesafen is obtained.

This application is a US National Stage application of InternationalApplication No. PCT/GB00/04731 filed Dec. 11, 2000, the contents ofwhich are incorporated herein by reference.

The present invention relates to a process for the production ofdiphenyl ether compounds which are useful as herbicides. In particular,it relates to a process for obtaining herbicidal diphenyl ether productson an industrial scale.

The problems associated with producing diphenyl ether herbicides on anindustrial scale are discussed in WO 97/10200 and WO 97/10199 in whichthere are disclosed processes for making compounds of formula

wherein R¹ is hydrogen or C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl(any of which may optionally be substituted with one or moresubstituents selected from halogen and OH) or COOH, COH, COOR⁴, COR⁶,CONR⁴R⁵ or CONHSO₂R⁴; R⁴ and R⁵ are each independently hydrogen or C₁-C₄alkyl optionally substituted with one or more halogen atoms; R⁶ is ahalogen atom or a group R⁴; R² is hydrogen or halo; R³ is C₁-C₄ alkyl,C₂-C₄ alkenyl or C₂-C₄ alkynyl, any of which may optionally besubstituted with one or more halogen atoms, or halo or, whereappropriate, a salt thereof. More especially the disclosures deal withthe commercially known herbicides5-(2-chloro-α,α,α-trifluoro-4-tolyloxy)-2-nitrobenzoic acid(acifluorfen) and5-(2-chloro-α,α,α-trifluoro-4-tolyloxy)-N-methanesulphonyl-2-nitrobenzamide(fomesafen).

A preferred method of making fomesafen on an industrial scale is viaacifluorfen which is made from5-(2-chloro-α,α,α-trifluoro-4-tolyloxy)-benzoic acid (CTTBA). Thiscompound is produced by oxidation of the corresponding tolyl compoundwhich is in turn obtained from the condensation of 3-hydroxybenzoic acidand 3,4-dichlorobenzotrifluoride.

Because the final product (fomesafen) is required in sufficient purityto meet strict product registration standards the process normally alsoinvolves one or more purification procedures.

The synthesis of acifluorfen and its conversion to fomesafen has beenthe subject of intensive research in an effort to improve one or more ofthe process steps. Thus for example in WO97/10200 there is disclosed apurification method for acifluorfen or fomesafen, while a set ofimproved nitration conditions is disclosed in WO97/10199. Another set ofpossible nitration conditions is disclosed in WO 98/19978. However noprocesses are known which can perform most or all of the above reactionsusing a single solvent. This is undoubtedly because the range ofreaction conditions is very demanding and it is not at all apparent if aprocess using a single common solvent is possible.

The applicants have now devised a single common solvent process in whichacifluorfen is converted to purified fomesafen. There is thereforeprovided a process for producing fomesafen from acifluorfen comprisingthe steps of

converting acifluorfen to its acid chloride

coupling the acid chloride so formed with methanesulphonamide (MSAM) toform crude fomesafen and

purifying the crude fomesafen characterised in that each of the steps iscarried out in a single common solvent.

The product of each step may be isolated at the end of the step or, morepreferably, the steps may be telescoped together so that there is noisolation until the purified fomesafen end product is obtained.

Suitable solvents are haloalkanes (such as 1,2-dichloroethane ortetrachloroethylene), halobenzenes (such as fluorobenzene, chlorobenzeneand dichlorobenzenes), alkoxybenzenes (such as anisole or phenetole),haloalkylbenzenes (such as benzotrifluoride), and esters (such as ethylacetate or butyl acetate). Preferred solvents are chloroalkanesespecially 1,2-dichloroethane (or ethylene dichloride or EDC).

In a further aspect of the invention the acifluorfen is formed bynitration of

CTTBA in the same solvent used to convert acifluorfen to fomesafen, thesolvent being a chloroalkane, especially EDC.

In yet a further aspect of the invention the CTTBA is formed by theoxidation of the corresponding toluene and the CTTBA is extracted fromthe reaction mass using the same solvent that is used to convertacifluorfen to fomesafen, the solvent being a chloroalkane, especiallyEDC.

The CTTBA is suitably generated by the oxidation of the correspondingtoluene using oxygen together with a catalyst (such as a cobalt orvanadium salt), at a temperature of 70° C. to 150° C.

The product of the extraction step and/or the nitration step may beisolated at the end of the step or, more preferably, the steps may betelescoped together so that there is no isolation of product at the endof each of the extraction and nitration stages.

In one suitable method for the nitration reaction, the nitrating agentmay be nitric acid or a mixture of nitric and sulphuric acids althoughother types of nitrating agent may also be used. It is also advantageousto conduct the reaction in the presence of acetic anhydride and, in thiscase, it is preferred that the molar ratio of acetic anhydride to CTTBAis from about 1:1 to 3:1. The reaction temperature may be from about−15° to 15° C., more usually from about −10° to 10° C. It isadvantageous to add the nitrating agent, over a period of time from 5 to15 hours, or, more preferably, 6 to 12 hours. Most preferably thereaction is carried out using a mixture of nitric and sulphuric acids at0-5° C. The resultant product solution is water washed, to removemineral acid and acetic acid then topped to remove residual water.

The conversion of acifluorfen to the acid chloride may be carried out byconventional methods, for example as set out in EP-A-0003416. It ispreferred to perform the reaction with a suitable chlorinating agentsuch as thionyl chloride or phosgene in the presence of a catalyst suchas triethylamine or dimethylformamide at temperature of 60 to 80° C.,preferably 70° C. The acid gases (SO₂ and HCl) may be removed, togetherwith excess of the chlorinating agent by addition and distillativeremoval of further organic solvent.

The acid chloride may then be reacted with methane sulphonamide to givefomesafen. This step may suitably be carried out by conventionalmethods, for example as set out in EP-A-0003416. In a preferred processthe acid chloride is coupled with MSAM using an excess of base such aspotassium carbonate at 60 to 80° C., preferably at 80° C. The inorganicby-products and excess MSAM are removed by washing with water. The finalproduct solution is topped to remove water. The organic solvent level,in the final product solution, is adjusted by topping off excess or byfurther additions and the product is then isolated by cooling to −10 to30° C. preferably 0° C.

A particular advantage in the use of EDC in the coupling reaction withMSAM is that the boiling point of the solvent is the upper temperaturelimit for process operation and thermal decomposition of the acidchloride during the reaction is avoided.

The product may then be purified using a chloroalkane solvent. Thepurification may suitably involve filtration and washing with coldsolvent or further recrystallisation from the solvent.

Using the process invention, it is possible to obtain fomesafen ofdesired quality in good yield enabling the industrial operation of theprocess with a single solvent.

The invention will now be further illustrated with reference to thefollowing examples.

EXAMPLE 1

The Preparation of Fomesafen in EDC

Step A

Extraction of 5-(2-chloro-α,α,α,-trifluoro-4-tolyloxy)-benzoic acid(CTTBA) from the Oxidation Reaction Mass

Materials

Mol Name Act wt Str % 100% wt Mol Wt Moles Ratio Oxidation mass* 498.5˜50 249.3 316.5 0.788 — 1,2-dichloroethane (EDC) 222.3 100 222.3 99 — —1,2-dichloroethane 816.6 100 816.6 99 — — (balance) Water 475 100 475 —— — *Composition of the topped oxidation mass was: 67% w/w CTTBAintermediate product 7% w/w organic impurities associated with CTTBA 25%w/w acetic acid

A 1 lb jar of the oxidation mass containing CTTBA was heated in a waterbath to 95° C. to melt the contents of the jar. The molten contents werethen charged to a 1 liter jacketed reaction vessel fitted with an anchoragitator, thermometer, Dean & Stark system with condenser and a nitrogenpurge applied via a bubbler at the top of the condenser. The reactor hadbeen pre-charged with warm water (475 ml at approx. 50° C.) which wasagitated during the addition of the molten batch. The product began tosolidify and EDC (175 ml) was charged at which point the deposited soliddissolved and partitioned between the two layers. The reactor contentswere heated to approx. 77° C. by external water bath circulation (bathat 80° C.) for 30 minutes before stopping the agitation and allowing thereactor contents to separate. The upper aqueous layer was removed bysuction and a warm water wash (506 ml) was charged to the reactor,stirred for 30 minutes and then settled before removing the upperaqueous layer as before. The reactor contents were then heated to refluxto remove residual water. After the system had been azeotropically drieda fixed ‘balance’ charge of EDC was made to dilute the CTTBA in EDCsolution to the safe concentration for the following nitration stage.

Yield: Product solution weight: 1326.9 g, Product solutionconcentration:  22.1% 100% wt of CTTBA isolated:  293.1 gm

Step B

Nitration of CTTBA to Acifluorfen

Materials

Mol Name Act wt Str % 100% wt Mol Wt Moles Ratio CTTBA ECD solution642.5 22.09 141.9 316.5 0.448 1.000 Sulphuric acid 98% 1.81 98 1.77 980.018 0.040 Acetic anhydride 90.11 100 90.11 102 0.883 1.972 Mixed acid# 115.0 33 37.95 63 0.602 1.345 # Mixed acid is a mixture of anhydrousnitric acid (33%) and sulphuric acid (67%) by weight.

The CTTBA solution in ECD (prepared as in step A) at 50° C., was chargedto a clean dry 1 liter jacketed split reaction vessel fitted withthermometer, turbine agitator, Dean & Stark system fitted with condenserand a nitrogen purge attached via a bubbler to the top of the condenser.The reactor contents were held at 50° C. by jacket circulation andagitated whilst the sulphuric acid was charged. The acetic anhydride wasthen charged and the reactor contents cooled to 0° C. by applyingexternal cooling to the reactor jacket. On reaching 0° C. the mixed acidwas slowly charged to the reactor, using a syringe pump and tefloncannular via a suba seal cap on the reactor, over a period ofapproximately 2 hrs. During this addition the temperature was controlledat 0-5° C. by periodically stopping the mixed acid addition. A samplewas withdrawn for HPLC after a further 15 minute stir to check forcompletion of nitration—the analysis showed that the reaction wascomplete and needed no further mixed acid addition. The reaction masswas then quenched with 250 ml of cold water—the temperature rose toapproximately 35° C. and the reaction mass allowed to stand overnightwithout heating or agitation. The following day work-up was effected byagitating the reactor contents whilst heating to 60° C. After an hourstir the agitation was stopped and the two phases allowed to separate.The upper pale yellow aqueous layer was then separated, from the lowerred organic layer, by suction. Two further 250 ml cold water washes werethen applied, the reactor contents then heated to 60° C., withagitation, and treated in the same manner as the first wash. Residualinterfacial material and water stayed with the organic phase afterseparation and the water was removed by agitating the reactor contents,heating the mixture to reflux via the Dean & Stark facilitatingseparation of the water and recycling the EDC.

Yield 89.2%

Step C

Chlorination to Acifluorfen Acid Chloride

Materials

Mol Name Act wt Str % 100% wt Mol Wt Moles Ratio Acifluorfen EDCsolution 653 22.1 144.3 361.5 0.399 1.000 Thionyl chloride (initial)76.7 99 75.9 119 0.638 1.600 Thionyl chloride (balance) 1.63 99 1.61 1190.014 0.035 Triethylamine 0.41 99 0.4 102 0.004 0.010 ECD purges 400 ml— — — — —

The acifluorfen in EDC solution at 50° C. was charged to a clean dry 1liter split reaction vessel fitted with turbine agitator, thermometer,Dean & Stark system fitted with condenser and a nitrogen purge fed in atthe top of the condenser via a bubbler. The reactor contents were heatedto 70° C. (by external bath heating—bath set at 75° C.) and agitated.The thionyl chloride was then charged, via syringe pump fitted with aTeflon cannular fed in through a suba seal on the reactor, over a periodof just under 2 hrs. After complete addition of the thionyl chloride thereactor contents were agitated and heated at 70° C. to ensure completereaction. A sample of the acid chloride was taken for analysis by GLC.The analysis showed a little unreacted AA was still present—a calculatedextra charge of thionyl chloride was added and the reaction heated untilall gas evolution stopped. The reaction product obtained containedthionyl chloride, sulphur dioxide and hydrogen chloride gas impurities.In order to remove these impurities two successive additions of EDC weremade, each addition being half the volume of the initial productsolution, the additional EDC was then removed by distillation.

Yield: 92.6%

Step D

Preparation of Fomesafen from Aciflourfen Acid Chloride

Materials

Mol Name Act wt Str % 100% wt Mol Wt Moles Ratio Methanesulphonamide11.51 99 11.39 95 0.120 1.000 EDC 403.4 — — — — — Potassium carbonate29.0 99 28.71 138 0.208 1.734 Acifluorfen acid chloride 120.3 23.5428.22 380 0.075 0.621 EDC for Acifluorfen acid 70 — — — — — chloride

The methanesulphonamide (MSAM) together with 70 gm of EDC were chargedto a clean dry 1 liter jacketed split reaction vessel fitted with aturbine agitator, thermometer, Dean & Stark fitted with condenser andnitrogen purge fed in via a bubbler on the condenser outlet. The mixturewas heated up to 80° C. whilst agitating at ˜400 rpm. Further EDC wasadded until the methanesulphonamide had dissolved at 80° C.—a further403.4 gm. Potassium carbonate was then charged to the reactor and theslurry stirred for a further 1 hr. The required AA acid chloride(prepared as in step C) was then mixed with EDC to dilute to an AA acidchloride concentration of ˜17%. The diluted acid chloride solution wasthen charged to the reactor slurry over ˜4 hrs. The reaction mass wasadjusted to 55° C., warm water (70 ml) added and the mixture stirred for30 minutes before stopping the agitation and allowing the two phases toseparate. The upper aqueous layer was removed by vacuum. A further warmwater wash was then applied (100 ml) stirred for 30 minutes thenseparated as with the first wash. The reactor contents were then heatedup to reflux and were azeotropically dried before the purificationstage. The weight of product solution was determined and analysiscarried out to determine the fomesafen yield.

Yield: 87.9 % approximate crude product composition 2′-nitro 10.8 pph6′-nitro  5.6 pph 5-CF₃  7.3 pph acifluorfen  4.3 pph

Step E

Purification of Fomesafen

Materials

Mol Name Act wt Str % 100% wt Mol Wt Moles Ratio fomesafen Crude in EDC546.7 5.2 28.37 438.5 0.065 1.000

The EDC solution of crude fomesafen, after azeotrope drying, was held at80° C. in a 1 liter jacketed reaction vessel fitted with thermometer,turbine agitator, Dean & Stark fitted with condenser and nitrogen purgefed in via a bubbler on the condenser outlet. The reactor contents wereagitated at 400 rpm and heated to reflux in order to remove EDC (200 mlremoved)—the circulating bath temperature was set to 98° C. to achievethis. In order to obtain purified fomesafen the agitation was reduced to100 rpm and the solution was cooled in 10° C. steps and holding for 15minutes for each step, down to a temperature of 0° C. At each step theagitation was stopped and the supernatant mother liquor sampled todetermine the product concentration. The reactor contents were thenfiltered on a sintered nutche and the reactor washed clean with a littlecold EDC which was then used to wash the product cake. The product cakewas then air dried.

Yield: 82.1% Strength: 88.8%. approximate crude product composition2′-nitro 0.4 pph 6′-nitro 0.2 pph 5-CF₃ 2.2 pph acifluorfen 0.4 pph${{where}\quad {pph}} = {\frac{{parts}\quad {of}\quad {impurity}}{{parts}\quad {of}\quad {fomesafen}} \times \frac{100}{1}}$

EXAMPLE 2

The Preparation of Fomesafen in Anisole

Step A

Conversion of Acifluourfen to its Acid Chloride

A 750 ml split reaction flask fitted with reflux condenser, thermometer,probe for bath controller and nitrogen purge was heated by an externaloil bath and connected to a caustic scrubber system. The reactor wascharged with acifluorfen (62.0 gm≡0.166 equivalents), dimethyl formamide(0.185 gm≡0.0025 equivalents) and anisole (242 gm). The mixture washeated to 70° C. and agitated. On achieving temperature thionyl chloride(26.4 gm≡0.215 equivalents) was charged over an hour by syringe pump.The reaction was then heated for a further 1.5 hour, after completeaddition of the thionyl chloride, to give a clear yellow solution. Thereaction mass was then allowed to self cool to 50° C., at which pointthe apparatus was configured for distillation and a total of 2.5 gm ofcontaminated anisole (containing thionyl chloride/HCl and SOCl₂) wasremoved (at approx. 50° C. pot temperature and 15 mbarpressure)—distillation was relatively smooth. Vacuum was relieved withnitrogen and the product solution bottled off and analysed by GLC.

Step B

Formation of Crude Fomesafen

A slurry of potassium carbonate (7.8 gm≡0.055 equivalents), anisole(48.6 gm) and Methane Sulphonamide (MSAM 3.22 gm≡0.0322 equivalents) wasagitated in a 250 ml split reaction vessel and heated on an oil bath to70° C. A portion of acifluorfen acid chloride (45 gm @ 22.2%≡0.0263equivalents) was charged to a syringe pump and then run into the MSAMslurry over a period of approximately 3.5 hours. The reaction was thenallowed to stir at 70° C. for 30 minutes then sampled to check forcompletion of reaction. The reaction was quenched with water (100 gm)and the two phases separated, extra water was required to improveseparation. The two layers were then separated and analysed giving ayield of 96.0% as fomesafen in the aqueous phase.

Step C

Purification of Crude Fomesafen

Crude dry fomesafen paste (9.66 gm) was charged, in small portions, toanisole (50 gm) contained in a 100 ml four necked flask fitted with athermometer and a ptfe paddle agitator. The slurry was agitated andheated, during the addition, with an oil bath to 130° C. Each portion ofpaste was charged after the previous sample had dissolved. When thesystem had reached saturation at 130° C. the reaction mass was allowedto self cool and crystallise. The resultant product slurry was filteredoff and the paste pulled ‘dry’ on a nutche before discharging, weighingand analysing.

A grey paste (4.6 gm) of solids 94.3% and strength on dry of 84.3% wasobtained giving a yield of 64% based on fomesafen charge.

What is claimed is:
 1. A process for producing fomesafen from5-(2-chloro-α,α,α,-trifluoro-4-tolyloxy-benzoic acid which comprises thesteps of: (i) Extracting5-(2-chloro-α,α,α,-trifluoro-4-tosyloxy)-benzoic acid from an oxidationreaction mass; (ii) nitrating5-(2-chloro-α,α,α,-trifluoro-4-tolyloxy)-benzoic acid to formacifluorfen (iii) converting acifluorfen to its acid chloride (iv)coupling the acid chloride so formed with methanesulphonamide (MSAM) inthe presence a base to form crude fomesafen and (v) purifying the crudefomesafen wherein each of the steps (i) to (iv) is carried out in asingle common chloroalkane solvent.
 2. A process according to claim 1wherein the steps are telescoped together so that there is no isolationof the product for any step until fomesafen is obtained.
 3. A processaccording to claim 1 in which the chloroalkane solvent is1,2-dichloroethane.
 4. A process according to claim 1 in which thenitration is performed using a nitrating agent comprising nitric acid ora mixture of nitric and sulphuric acids and in which the reaction takesplace in the presence of acetic anhydride, the molar ratio of5-(2-chloro-α,α,α,-trifluoro-4-tolyloxy) benzoic acid to aceticanhydride being from about 1:1 to 3:1.
 5. A process according to claim 1wherein the 5-(2-chloro-α,α,α,-trifluoro-4-tolyloxy)-benzoic acid isgenerated by oxidation of the corresponding toluene using oxygentogether with a catalyst at a temperature of from 70° C. to 150° C. toform a reaction mass from which the5-(2-chloro-α,α,α,-trifluoro-4-tolyloxy)-benzoic acid is extracted.